A20 Haploinsufficiency Aggravates Transplant Arteriosclerosis in Mouse Vascular Allografts: Implications for Clinical Transplantation. Issue 11 (November 2016)

• Record Type: Journal Article
• Authors: Moll, Herwig P.; Lee, Andy; Peterson, Clayton R.; Revuelta Cervantes, Jesus; Wojcik, Brandon M.; Parulkar, Anshul; Mele, Alessandra; LoGerfo, Philip J.; Siracuse, Jeffrey J.; Csizmadia, Eva; da Silva, Cleide G.; Ferran, Christiane
• Is Part Of: Transplantation. Volume 100:Issue 11(2016)
• Publication Date: 2016-11
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/TP.0000000000001407
• Languages: English
• ISSNs: 0041-1337

Abstract

Abstract : Background: Inflammation is central to the pathogenesis of transplant arteriosclerosis (TA). We questioned whether physiologic levels of anti-inflammatory A20 influence TA severity. Methods: We performed major histocompatibility complex mismatched aorta to carotid artery interposition grafts, using wild type (WT) or A20 heterozygote (HET) C57BL/6 (H-2 b ) donors and BALB/c (H-2 d ) recipients, and conversely BALB/c donors and WT/HET recipients. We analyzed aortic allografts by histology, immunohistochemistry, immunofluorescence, and gene profiling (quantitative real-time reverse-transcriptase polymerase chain reaction). We validated select in vivo A20 targets in human and mouse smooth muscle cell (SMC) cultures. Results: We noted significantly greater intimal hyperplasia in HET versus WT allografts, indicating aggravated TA. Inadequate upregulation of A20 in HET allografts after transplantation was associated with excessive NF-кB activation, gauged by higher levels of IkBα, p65, VCAM-1, ICAM-1, CXCL10, CCL2, TNF, and IL-6 (mostly localized to SMC). Correspondingly, cytokine-induced upregulation of TNF and IL-6 in human and mouse SMC cultures inversely correlated with A20 expression. Aggravated TA in HET versus WT allografts correlated with increased intimal SMC proliferation, and a higher number of infiltrating IFNγ + and Granzyme B + CD4 + T cells and natural killer cells, and lower number of FoxP3 + regulatory T cells. A20 haploinsufficiency in allograft recipients did not influence TA. Conclusions: A20 haploinsufficiency in vascular allografts aggravates lesions of TA by exacerbating inflammation, SMC proliferation, and infiltration of pathogenic T cells. A20 single nucleotide polymorphisms associating with lower A20 expression or function in donors of vascularized allografts may inform risk and severity of TA, highlighting the clinical implications of our findings. Abstract : Moll et al report that ubiquitin-editing protein A20 haploinsufficiency in vascular allografts aggravates transplant atheriosclerosis in a C57BL/6 aorta to BALB/c carotid artery interposition transplant model, by exacerbating inflammation, smooth muscle cell proliferation and the infiltration of pathogenic T cells. Supplemental digital content is available in the text.